The male genital tract constitutes a major site of HIV-1 infection worldwide. Therefore, blocking HIV-1 infection in the penile mucosa is integral to curbing the global AIDS epidemic. Effective intervention strategies to prevent the sexual transmission of HIV-1 most likely will need to interrupt viral infection during the earliest stages of mucosal transmission. One of the barriers to developing an effective AIDS vaccine/microbicide is a lack of understanding of the early pathogenesis in the establishment of mucosal HIV-1 infection. Although the majority of the 15 million HIV-infected men worldwide acquired infection via the penile mucosa, very little is known about the precise routes of viral entry into the male genital compartment. Furthermore, the biologic basis underlying the protective effect of male circumcision in preventing HIV-1 acquisition in heterosexual men remains unclear. Understanding the initial events of viral entry and dissemination during acute HIV-1 infection in the penile mucosa is critical for the design of intervention strategies to block HIV-1 mucosal transmission in the male genital tract. Our overall goal is to elucidate the immunopathogenesis of penile mucosal transmission, an important but neglected area of HIV/AIDS research. Understanding the early events associated with HIV-1 acquisition in the male genital tract has been hampered by the lack of a physiologically-relevant animal penile transmission model. To date, no reliable, well-characterized simian immunodeficiency virus (SIV)/rhesus monkey prepuce infection model has been published. The reason for the absence of this transmission model is that it has been technically very difficult to initiate penile infection in nonhuman primates (NHP). To overcome this hurdle, we exploited our recent understanding that TRIM5 alleles play a role in modulating mucosal acquisition of SIV in Indian-origin rhesus monkeys. We have developed a technique for atraumatically exposing the penile mucosa to SIV and demonstrated that systemic SIV infection can be achieved after prepuce exposures in rhesus monkeys that are relatively more permissive to mucosal infection on the basis of their TRIM5 genotypes. In this R21 application, our objective is to utilize this novel SIV/rhesus monkey penile infection model to study HIV-1 pathogenesis in the male genital tract. To accomplish this, we will first refine this SIV penile transmission model and determine whether it recapitulates key virologic and immunologic features of mucosal HIV-1 infection. We will then use this system to explore the early events of HIV/SIV pathogenesis in the penile mucosa. The data from these studies will demonstrate the validity of the SIV/rhesus monkey penile transmission model, illuminate the mechanisms of HIV-1 transmission in the penile mucosa, and form a foundation to dissect the mucosal immunopathogenesis of HIV-1 infection during acute infection in the male genital compartment. These insights will provide the biologic basis for developing rational interventions that prevent HIV-1 sexual transmission in men. PUBLIC HEALTH RELEVANCE: Although the majority of the HIV-infected men worldwide acquired infection via the penile mucosa, very little is known about the precise routes of viral entry into the male reproductive tract. We will use a novel SIV/rhesus monkey model of penile infection to elucidate the mechanisms of HIV-1 mucosal transmission in the male genital tract. This animal mucosal transmission model has the potential to have a transformative impact on developing intervention strategies to block HIV-1 acquisition in the human male genital mucosa.